Bupropion as a modulator of drug activity

ABSTRACT

This disclosure relates to methods administering bupropion or a prodrug thereof in conjunction with dextromethorphan to a human being. Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and bupropion or a prodrug of bupropion are also disclosed.

SUMMARY

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administering bupropion or aprodrug thereof, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin an AUC₀₋₁₂ of dextromethorphan that is at least about 40 ng·hr/mL.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being, comprising co-administering bupropion or aprodrug thereof, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin a C_(max) of dextromethorphan that is at least about 6 ng/mL.

Some embodiments include method of increasing dextromethorphan plasmalevels in a human being, comprising co-administering bupropion or aprodrug thereof, with dextromethorphan to the human being, wherein thebupropion or a prodrug thereof is administered in an amount that resultsin a C_(avg) of dextromethorphan, over the period between two separateand consecutive administrations of dextromethorphan, that is at leastabout 5 ng/mL. prodrug

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering threohydroxybupropion, ora prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as threohydroxybupropion.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering threohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result being treated with dextromethorphan.

Some embodiments include an oral sustained release delivery system fordextromethorphan, comprising bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, dextromethorphan, and a water soluble vehicle.

Some embodiments include a method of decreasing the number of doses ofdextromethorphan that can be administered without loss of efficacy,comprising orally administering an effective amount of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or aprodrug of any of these compounds, to a human being in need of treatmentwith dextromethorphan.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that threohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of treatment withdextromethorphan, wherein a decrease in the dextrorphan plasma leveloccurs on the first day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion and dextromethorphanare co-administered, as compared to the same amount of dextromethorphanadministered without bupropion.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that erythrohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least eight consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the eighth day, the dextrorphanplasma level is lower than the dextrorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Antidepressant compounds, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, can be used to improve thetherapeutic properties, such as in the treatment of neurologicaldisorders, of dextromethorphan. Bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, regardless of stereochemistry, can beeffective in inhibiting or reducing the metabolism of dextromethorphanin some human beings. This may be accomplished by co-administeringbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan.

Some embodiments include a method of treating a neurological disordercomprising administering an antidepressant compound and dextromethorphanto a human being in need thereof, wherein the human being is anextensive metabolizer of dextromethorphan.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering bupropion with dextromethorphan to the humanbeing.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering bupropion to a human beingin need of treatment with dextromethorphan, wherein the human being isan extensive metabolizer of dextromethorphan, and whereindextromethorphan is present in the body of the human being at the sametime as bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering bupropion to a human being inneed thereof.

Some embodiments include a method of improving the antitussiveproperties of dextromethorphan comprising administering bupropion inconjunction with administration of dextromethorphan to a human being inneed of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of bupropion and dextromethorphan to a humanbeing in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering bupropion and dextromethorphan to a human beingin need thereof, wherein the bupropion and dextromethorphan areadministered at least once a day for at least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering about 150 mg/day to about 300 mg/day ofbupropion and about 15 mg/day to about 60 mg/day of dextromethorphan toa human being in need thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering hydroxybupropion, or a prodrug thereof, withdextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering erythrohydroxybupropion, or a prodrugthereof, with dextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering threohydroxybupropion, or a prodrug thereof,with dextromethorphan to the human being.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time ashydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time aserythrohydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time asthreohydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as hydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering erythrohydroxybupropion,or a prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as erythrohydroxybupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days ofco-administration of bupropion with dextromethorphan, wherein anincrease in the dextromethorphan plasma level occurs on the first daythat bupropion and dextromethorphan are co-administered, as compared tothe same amount of dextromethorphan administered without bupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of co-administrationof hydroxybupropion, or a prodrug thereof, with dextromethorphan,wherein an increase in the dextromethorphan plasma level occurs on thefirst day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of erythrohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of threohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that threohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least five consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the fifth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for five consecutivedays.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least six consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the sixth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering bupropion withdextromethorphan to a human patient in need of treatment withdextromethorphan, wherein dextromethorphan has a plasma level 12 hoursafter co-administering bupropion with dextromethorphan that is at leasttwice the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering hydroxybupropion, or aprodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering hydroxybupropion, or a prodrugthereof, with dextromethorphan that is at least twice the plasma levelthat would be achieved by administering the same amount ofdextromethorphan without hydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering erythrohydroxybupropion,or a prodrug thereof, with dextromethorphan to a human patient in needof treatment with dextromethorphan, wherein dextromethorphan has aplasma level 12 hours after co-administering erythrohydroxybupropion, ora prodrug thereof, with dextromethorphan that is at least twice theplasma level that would be achieved by administering the same amount ofdextromethorphan without erythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering threohydroxybupropion, ora prodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering threohydroxybupropion, or aprodrug thereof, with dextromethorphan that is at least twice the plasmalevel that would be achieved by administering the same amount ofdextromethorphan without threohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering bupropion and dextromethorphan to a human patient inneed of dextromethorphan treatment, wherein the human patient is at riskof experiencing the adverse event as a result being treated withdextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering erythrohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by bupropion, comprising co-administeringdextromethorphan and bupropion to a human patient in need of bupropiontreatment, wherein the human patient is at risk of experiencing theadverse event as a result being treated with bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering bupropion in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering hydroxybupropion, or a prodrugthereof, in conjunction with administration of dextromethorphan to ahuman being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering erythrohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering threohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of hydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering bupropion and dextromethorphan to a human beingin need thereof, wherein the bupropion and dextromethorphan areadministered at least once a day for at least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human being in need thereof, wherein the bupropionand dextromethorphan are administered at least once a day for at least 8days.

Some embodiments include a method of treating a neurological disordercomprising administering erythrohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein thebupropion and dextromethorphan are administered at least once a day forat least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering threohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein thebupropion and dextromethorphan are administered at least once a day forat least 8 days.

Some embodiments include a pharmaceutical composition, dosage form, ormedicament comprising a therapeutically effective amount ofdextromethorphan, a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, and a pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the mean plasma concentrations of dextromethorphanover time after dosing on Day 8 for subjects administereddextromethorphan alone or dextromethorphan and bupropion.

FIG. 2 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 3 depicts mean AUC₀₋₂₄ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 4 depicts mean AUC_(0-inf) of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone as compared todextromethorphan and bupropion.

FIG. 6 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 7 depicts mean dextromethorphan trough plasma concentrations forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 8 depicts mean dextromethorphan maximum plasma concentrations onDay 1 and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 9 is a plot of the mean plasma concentrations of dextrorphan overtime after dosing on Day 8 for subjects administered dextromethorphanalone or dextromethorphan and bupropion.

FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 11 depicts mean AUC₀₋₁₂ of dextrorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 12 depicts the potency of various antidepressant compounds forinhibition of the metabolism of dextromethorphan in human livermicrosomes.

DETAILED DESCRIPTION

Some embodiments include a method of treating neurological disorderscomprising administering a therapeutically effective amount ofdextromethorphan and a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, to a person in need thereof.

Some embodiments include a method of enhancing the therapeuticproperties of dextromethorphan in treating neurological disorders,comprising co-administering dextromethorphan and an antidepressant, suchas bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being that is an extensive metabolizer ofdextromethorphan, comprising co-administering an antidepressantcompound, such as bupropion, and dextromethorphan to the human being.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time as theantidepressant.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, including increasing the elimination half life(T_(1/2)) of dextromethorphan. These embodiments may compriseadministering an antidepressant compound, such as bupropion, to a humanbeing, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as the antidepressant compound.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being in need thereof, such as a humanbeing in need of treatment for pain.

Some embodiments include a method of improving the therapeuticproperties of dextromethorphan in treating neurological disorderscomprising administering an antidepressant compound, such as bupropion,in conjunction with administration of dextromethorphan to a human beingin need of treatment for a neurological disorder.

Some embodiments include a method of treating neurological disorderscomprising administering a combination of an antidepressant compound,such as bupropion, and dextromethorphan to a human being in needthereof.

Co-administration of an antidepressant compound, such as bupropion,hydroxbupropion, threohydroxybupropion, erythrohydroxybupropion, or aprodrug of the antidepressant compound, with dextromethorphan may occurone or more times for a single day, or for 2, 3, 4, 5, 6, 7, 8, 14, 30,60, 90, or more consecutive days. In some embodiments, co-administrationis at least daily for at least two consecutive days.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as a cough suppressant. According to the FDA'sdextromethorphan product labeling requirement under the OTC Monograph[21CFR341.74], dextromethorphan should be dosed 6 times a day (every 4hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).

Dextromethorphan is rapidly metabolized in the human liver. This rapidhepatic metabolism may limit systemic drug exposure in individuals whoare extensive metabolizers. Human beings can be: 1) extensivemetabolizers of dextromethorphan—those who rapidly metabolizedextromethorphan; 2) poor metabolizers of dextromethorphan—those whoonly poorly metabolize dextromethorphan; or 3) intermediate metabolizersof dextromethorphan—those whose metabolism of dextromethorphan issomewhere between that of an extensive metabolizer and a poormetabolizer. Extensive metabolizers can also be ultra-rapidmetabolizers. Extensive metabolizers of dextromethorphan are asignificant portion of the human population. Dextromethorphan can, forexample, be metabolized to dextrorphan.

When given the same oral dose of dextromethorphan, plasma levels ofdextromethorphan are significantly higher in poor metabolizers orintermediate metabolizers as compared to extensive metabolizers ofdextromethorphan. The low plasma concentrations of dextromethorphan canlimit its clinical utility as a single agent for extensive metabolizers,and possibly intermediate metabolizers, of dextromethorphan. Someantidepressants, such as bupropion, inhibit the metabolism ofdextromethorphan, and can thus improve its therapeutic efficacy.Similarly, antidepressants may allow dextromethorphan to be given lessoften, such as once a day instead of twice a day, once a day instead ofthree times a day, once a day instead of four times a day, twice a dayinstead of three times a day, or twice a day instead of four times aday, without loss of therapeutic efficacy.

Co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan may enhance the mechanisms of action, or pharmacologicalproperties of dextromethorphan and dextrorphan. Mechanisms of action ofdextromethorphan and dextrorphan can include sigma-1 agonist and NMDAantagonist properties, calcium channel blockade, muscarinic binding,serotonin transporter (5HTT) inhibition, and mu receptor potentiation.

Some embodiments include co-administration of an antidepressant such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, with dextromethorphan or dextrorphan to agonize, antagonize,or modulate a sigma-1 receptor, or an NMDA receptor; to block a calciumchannel; to bind to a muscarinic receptor; to inhibit a serotonintransporter (5HTT); or to potentiate a mu receptor.

Pharmacological properties of dextromethorphan and dextrorphan caninclude NMDA high-affinity site, NMDR-2A, and functional NMDR-2Breceptor antagonism, sigma-1 stimulation, putative mTOR activation (bysigma-1 stimulation, mu potentiation, beta adrenoreceptor stimulation,and 5HTT inhibition), putative AMPA receptor trafficking (by mTORactivation, PCP antagonism, sigma-1 stimulation, beta stimulation, mupotentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis,synaptogenesis, and neuronal survival by NMDA antagonism and sigma-1 andmTOR signaling. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate an NMDA high-affinity site, NMDR-2A, afunctional NMDR-2B receptor, sigma-1 receptor, a putative mTOR receptor(such as by stimulating sigma-1, potentiating a mu receptor, stimulatinga beta adrenoreceptor, or inhibiting a 5HTT), or a putative AMPAreceptor (such as by activating mTOR, antagonizing PCP activity,stimulating a sigma-1 receptor, stimulating a beta adrenergic receptor,potentiating a mu receptor, or inhibiting 5HTT). Some embodimentsinclude co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan to cause, increase, decrease, or otherwise modulatedendritogenesis, spinogenesis, or synaptogenesis. Some embodimentsinclude co-administration of an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, with dextromethorphanor dextrorphan to cause, increase, decrease, or otherwise modulateneuronal survival by NMDA antagonism and/or sigma-1 and/or mTORsignaling.

Pharmacological properties of dextromethorphan and dextrorphan caninclude 5HTT and norepinephrine transporter inhibition, sigma-1stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/dreceptor stimulation. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate the 5HTT and/or norepinephrinetransporter, the sigma-1 receptor, NMDA and/or PCP receptor, and/or tostimulate the serotonin 5HT1b/d receptor.

Additional properties for dextromethorphan and dextrorphan can includepossible presynaptic alpha-2 adrenoreceptor antagonism or postsynapticalpha-2 stimulation, beta stimulation and possible muscarinic and muantagonism. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto bind to, agonize, antagonize, stimulate, activate, inhibit, influencethe trafficking of, or modulate a presynaptic alpha-2 adrenoreceptor,postsynaptic alpha-2 receptor, beta adrenoreceptor, muscarinic receptor,or mu receptor. Dextromethorphan and dextrorphan may be glial cellmodulators. Some embodiments include co-administration of anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan or dextrorphanto modulate glial cells.

Pain or other neurological disorders may be treated by a methodcomprising administering a therapeutically effective amount ofdextromethorphan and a therapeutically effective amount of anantidepressant compound, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, to a person in need thereof.

Examples of neurological disorders that may be treated, or that may betreated with increased efficacy, by a combination of dextromethorphanand an antidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, include, but are not limited to:affective disorders, psychiatric disorders, cerebral function disorders,movement disorders, dementias, motor neuron diseases, neurodegenerativediseases, seizure disorders, and headaches.

Affective disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, include, but are notlimited to, depression, major depression, treatment-resistant depressionand treatment-resistant bipolar depression, bipolar disorders includingcyclothymia, seasonal affective disorder, mood disorders, mania, anxietydisorders, attention deficit disorder (ADD), attention deficit disorderwith hyperactivity (ADDH), and attention deficit/hyperactivity disorder(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder,bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by changes in mood, feelings of intensesadness, despair, mental slowing, loss of concentration, pessimisticworry, agitation, and self-deprecation. Physical symptoms of depressionmay include insomnia, anorexia, weight loss, decreased energy andlibido, and abnormal hormonal circadian rhythms.

Psychiatric disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, include, but are notlimited to, anxiety disorders, including but not limited to, phobias,generalized anxiety disorder, social anxiety disorder, panic disorder,agoraphobia, obsessive-compulsive disorder, and post-traumatic stressdisorder (PTSD); mania, manic depressive illness, hypomania, unipolardepression, depression, stress disorders, somatoform disorders,personality disorders, psychosis, schizophrenia, delusional disorder,schizoaffective disorder, schizotypy, aggression, aggression inAlzheimer's disease, agitation, and agitation in Alzheimer's disease.

Substance addiction abuse that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, includes, but is notlimited to, drug dependence, addiction to cocaine, psychostimulants(e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids,anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines,hallucinogens, phencyclidine, volatile solvents, and volatile nitrites.Nicotine addiction includes nicotine addiction of all known forms, suchas smoking cigarettes, cigars and/or pipes, and addiction to chewingtobacco.

Cerebral function disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, disorders involving intellectual deficits such as seniledementia, Alzheimer's type dementia, memory loss, amnesia/amnesticsyndrome, epilepsy, disturbances of consciousness, coma, lowering ofattention, speech disorders, voice spasms, Parkinson's disease,Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, andschizophrenia. Cerebral function disorders also include disorders causedby cerebrovascular diseases including, but not limited to, stroke,cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,cerebral venous thrombosis, head injuries, and the like where symptomsinclude disturbance of consciousness, senile dementia, coma, lowering ofattention, and speech disorders.

Movement disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, akathisia, akinesia, associated movements, athetosis,ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea,Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia,tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis,dopamine-responsive dystonia, Parkinson's disease, restless legssyndrome (RLS), tremor, essential tremor, and Tourette's syndrome, andWilson's disease.

Dementias that may be treated by a combination of dextromethorphan andan antidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds include, but are not limited to,Alzheimer's disease, Parkinson's disease, vascular dementia, dementiawith Lewy bodies, mixed dementia, fronto-temporal dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington'sdisease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, amyotrophic lateral sclerosis (ALS), progressive bulbarpalsy, primary lateral sclerosis (PLS), progressive muscular atrophy,post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motoratrophies, Tay-Sach's disease, Sandoff disease, and hereditary spasticparaplegia.

Neurodegenerative diseases that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to Alzheimer's disease, prion-related diseases, cerebellarataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA),bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewybody disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS orLou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy,Shy-Drager syndrome, corticobasal degeneration, progressive supranuclearpalsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebralautosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Toothdisease (CMT), familial spastic paraparesis, neurofibromatosis,olivopontine cerebellar atrophy or degeneration, striatonigraldegeneration, Guillain-Barré syndrome, and spastic paraplesia.

Seizure disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, epileptic seizures, nonepileptic seizures, epilepsy, febrileseizures; partial seizures including, but not limited to, simple partialseizures, Jacksonian seizures, complex partial seizures, and epilepsiapartialis continua; generalized seizures including, but not limited to,generalized tonic-clonic seizures, absence seizures, atonic seizures,myoclonic seizures, juvenile myoclonic seizures, and infantile spasms;and status epilepticus.

Types of headaches that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, migraine, tension, and cluster headaches.

Other neurological disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, Rett Syndrome,autism, tinnitus, disturbances of consciousness disorders, sexualdysfunction, intractable coughing, narcolepsy, cataplexy; voicedisorders due to uncontrolled laryngeal muscle spasms, including, butnot limited to, abductor spasmodic dysphonia, adductor spasmodicdysphonia, muscular tension dysphonia, and vocal tremor; diabeticneuropathy, chemotherapy-induced neurotoxicity, such as methotrexateneurotoxicity; incontinence including, but not limited, stress urinaryincontinence, urge urinary incontinence, and fecal incontinence; anderectile dysfunction.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may be used to treat pain,pseudobulbar affect, depression (including treatment resistantdepression), disorders related to memory and cognition, schizophrenia,Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett'ssyndrome, seizures, cough (including chronic cough), etc.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat treatmentrefractory depression.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat allodynia.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat treatmentrefractory hyperalgesia.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat dermatitis.

Pain relieving properties of dextromethorphan may be enhanced by amethod comprising co-administering dextromethorphan and anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan.

Pain relieving properties of bupropion may be enhanced by a methodcomprising co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments ketamine or another NMDA receptor antagonist may beadministered with an antidepressant, such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments dextromethorphan and quinidine may beco-administered with an antidepressant, such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

These methods may be used to treat, or provide relief to, any type ofpain including, but not limited to, musculoskeletal pain, neuropathicpain, cancer-related pain, acute pain, nociceptive pain, inflammatorypain, arthritis pain, complex regional pain syndrome, etc.

In some embodiments, co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be used to treat orreduce inflammation or inflammatory conditions, such as Chron's disease,including pain associated with inflammation.

In some embodiments, co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be used to treatpsoriasis, cancer, viral infection, or as an adjuvant treatment formultiple myeloma.

Examples of musculoskeletal pain include low back pain (i.e. lumbosacralpain), primary dysmenorrhea, and arthritic pain, such as pain associatedwith rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, axial spondyloarthritis including ankylosingspondylitis, pain associated with vertebral crush fractures, fibrousdysplasia, osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered orally to relievemusculoskeletal pain including low back pain, and pain associated withrheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, axialspondyloarthritis including ankylosing spondylitis, Paget's disease,fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip,vertebral crush fractures, osteoporosis, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relieveinflammatory pain including musculoskeletal pain, arthritis pain, andcomplex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, is used to treat chronicmusculoskeletal pain.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relievecomplex regional pain syndrome, such as complex regional pain syndrometype I (CRPS-I), complex regional pain syndrome type II (CRPS-II),CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain.CRPS can also have a neuropathic component. Complex regional painsyndrome is a debilitating pain syndrome. It is characterized by severepain in a limb that can be accompanied by edema, and autonomic, motorand sensory changes.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered orally to relieveneuropathic pain.

Examples of neuropathic pain include diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, central pain, etc. Other causes of neuropathic paininclude cancer-related pain, lumbar nerve root compression, spinal cordinjury, post-stroke pain, central multiple sclerosis pain,HIV-associated neuropathy, and radio- or chemo-therapy associatedneuropathy, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, may be administered to relievefibromyalgia.

The term “treating” or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

Any antidepressant may be used in combination with dextromethorphan toimprove the therapeutic properties of dextromethorphan. Dextromethorphanand the antidepressant compound may be administered in separatecompositions or dosage forms, or may be administered in a singlecomposition or dosage form comprising both.

Antidepressant compounds that can be co-administered withdextromethorphan include, but are not limited to, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion,clomipramine, doxepin, fluoxetine, mianserin, imipramine,2-chloroimipramine, amitriptyline, amoxapine, desipramine,protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine,isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram,sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine,venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone,selegiline, sibutramine, milnacipran, tesofensine, brasofensine,moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone,butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol,norfluoxetine, dapoxetine, etc., or a metabolite or prodrug of any ofthese compounds, or a pharmaceutically acceptable salt of any of thesecompounds.

Bupropion has the structure shown below (bupropion hydrochloride formshown).

Combining bupropion with dextromethorphan may provide greater efficacy,such as greater pain relief, than would otherwise be achieved byadministering either component alone. In extensive metabolizers,dextromethorphan can be rapidly and extensively metabolized, yieldinglow systemic exposure even at high doses. Bupropion, besides possessinganti-depressant and analgesic properties, is an inhibitor ofdextromethorphan metabolism. Bupropion is a dopamine and norepinephrinereuptake inhibitor. It can also be a nicotinic acetylcholine receptorantagonist, and it can modulate cytokine associated with inflammatorydiseases. Bupropion can affect levels of tumor necrosis factor-alpha andinterferon-gamma. Metabolites of bupropion, which includehydroxybupropion, threohydroxybupropion (also known asthreohydrobupropion or threodihydrobupropion), anderythrohydroxybupropion (also known as erythrohydrobupropion orerythrodihydrobupropion), are also inhibitors of dextromethorphanmetabolism. Thus, bupropion, including a form of bupropion that israpidly converted in the body (such as a salt, hydrate, solvate,polymorph, etc.), is a prodrug of hydroxybupropion, threohydrobupropion,and erythrohydrobupropion. Prodrugs of bupropion can includeN-methylbupropion and N-benzylbupropion.

As explained above, this inhibition may augment dextromethorphan plasmalevels, resulting in additive or synergistic efficacy such as relief ofneurological disorders including pain, depression, smoking cessation,etc. Thus, while inhibition of dextromethorphan metabolism is only oneof many potential benefits of the combination, co-administration ofdextromethorphan with bupropion may thereby enhance the efficacy ofbupropion for many individuals. Co-administration of dextromethorphanwith bupropion may enhance the analgesic properties of bupropion formany individuals. Co-administration of dextromethorphan with bupropionmay also enhance the antidepressant properties of bupropion for manyindividuals, including faster onset of action.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as somnolence, associated with treatment bydextromethorphan. This may be useful, for example, in human patients atrisk of experiencing the adverse event as a result being treated withdextromethorphan.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as seizure, associated with treatment by bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds. This may be useful, forexample, in human patients at risk of experiencing the adverse event asa result being treated with bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

With respect to dextromethorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, co-administration may reduce acentral nervous system adverse event, a gastrointestinal event, oranother type of adverse event associated with any of these compounds.Central nervous system (CNS) adverse events include, but are not limitedto, nervousness, dizziness, sleeplessness, light-headedness, tremor,hallucinations, convulsions, CNS depression, fear, anxiety, headache,increased irritability or excitement, tinnitus, drowsiness, dizziness,sedation, somnolence, confusion, disorientation, lassitude,incoordination, fatigue, euphoria, nervousness, insomnia, sleepingdisturbances, convulsive seizures, excitation, catatonic-like states,hysteria, hallucinations, delusions, paranoia, headaches and/ormigraine, and extrapyramidal symptoms such as oculogyric crisis,torticollis, hyperexcitability, increased muscle tone, ataxia, andtongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea,vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominaldistension, flatulence, peptic ulcers with bleeding, loose stools,constipation, stomach pain, heartburn, gas, loss of appetite, feeling offullness in stomach, indigestion, bloating, hyperacidity, dry mouth,gastrointestinal disturbances, and gastric pain.

Co-administering dextromethorphan and an antidepressant, such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, does not necessarily require that the two compounds beadministered in the same dosage form. For example, the two compounds maybe administered in a single dosage form, or they may be administered intwo separate dosage forms. Additionally, the two compounds may beadministered at the same time, but this is not required. The compoundscan be given at different times as long as both are in a human body atthe same time for at least a portion of the time that treatment byco-administration is being carried out.

In some embodiments, co-administration of a combination of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, and dextromethorphanresults in both bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan contributing to the pain relievingproperties of the combination. For example, the combination may haveimproved pain relieving properties as compared to bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, alone or compared todextromethorphan alone, including potentially faster onset of action.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, alone.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to as compared to dextromethorphan alone.

Unless otherwise indicated, any reference to a compound herein, such asdextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, by structure, name, or any other means, includespharmaceutically acceptable salts; alternate solid forms, such aspolymorphs, solvates, hydrates, etc.; tautomers; deuterium modifiedcompounds, such as deuterium modified dextromethorphan; or any chemicalspecies that may rapidly convert to a compound described herein underconditions in which the compounds are used as described herein.

Examples of deuterium modified dextromethorphan include, but are notlimited to, those shown below.

A dosage form or a composition may be a blend or mixture ofdextromethorphan and a compound that inhibits the metabolism ofdextromethorphan, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, either alone or within a vehicle. Forexample, dextromethorphan and bupropion may be dispersed within eachother or dispersed together within a vehicle. A dispersion may include amixture of solid materials wherein small individual particles aresubstantially one compound, but the small particles are dispersed withinone another, such as might occur if two powders of two different drugsare blended with a solid vehicle material, and the blending is done inthe solid form. In some embodiments, dextromethorphan and bupropion maybe substantially uniformly dispersed within a composition or dosageform. Alternatively, dextromethorphan and bupropion may be in separatedomains or phases within a composition or dosage form. For example, onedrug may be in a coating and another drug may be in a core within thecoating. For example, one drug may be formulated for sustained releaseand another drug may be formulated for immediate release.

Some embodiments include administration of a tablet that containsbupropion in a form that provides sustained release and dextromethorphanin a form that provides immediate release. While there are many waysthat sustained release of bupropion may be achieved, in some embodimentsbupropion is combined with hydroxypropyl methylcellulose. For example,particles of bupropion hydrochloride could be blended withmicrocrystalline cellulose and hydroxypropyl methylcellulose (e.gMETHOCEL®) to form an admixture of blended powders. This could then becombined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or an antidepressant, such as bupropion,hydroxybupropion, threohydrobupropion and erythrohydrobupropion, or anon-bupropion antidepressant (all of which are referred to collectivelyherein as “therapeutic compounds” for convenience) may be combined witha pharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice as described, forexample, in Remington's Pharmaceutical Sciences, 2005. The relativeproportions of active ingredient and carrier may be determined, forexample, by the solubility and chemical nature of the compounds, chosenroute of administration and standard pharmaceutical practice.

Therapeutic compounds may be administered by any means that may resultin the contact of the active agent(s) with the desired site or site(s)of action in the body of a patient. The compounds may be administered byany conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. For example, they may be administeredas the sole active agents in a pharmaceutical composition, or they canbe used in combination with other therapeutically active ingredients.

Therapeutic compounds may be administered to a human patient in avariety of forms adapted to the chosen route of administration, e.g.,orally or parenterally. Parenteral administration in this respectincludes administration by the following routes: intravenous,intramuscular, subcutaneous, intraocular, intrasynovial, transepithelialincluding transdermal, ophthalmic, sublingual and buccal; topicallyincluding ophthalmic, dermal, ocular, rectal and nasal inhalation viainsufflation, aerosol and rectal systemic.

The ratio of dextromethorphan to bupropion may vary. In someembodiments, the weight ratio of dextromethorphan to bupropion may beabout 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or anyratio in a range bounded by, or between, any of these values. A ratio of0.1 indicates that the weight of dextromethorphan is 1/10 that ofbupropion. A ratio of 10 indicates that the weight of dextromethorphanis 10 times that of bupropion.

The amount of dextromethorphan in a therapeutic composition may vary.For example, some liquid compositions may comprise about 0.0001% (w/v)to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% toabout 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v)to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) toabout 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), or about 40% (w/v) to about 50% (w/v) ofdextromethorphan.

Some liquid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mgto about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg,about 120 mg, or about 180 mg of dextromethorphan, or any amount ofdextromethorphan in a range bounded by, or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.

Some solid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mgto about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120mg, or about 180 mg of dextromethorphan, or any amount ofdextromethorphan in a range bounded by, or between, any of these values.

The amount of bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, in a therapeutic composition may vary. If increasing theplasma level of dextromethorphan is desired, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, should be administeredin an amount that increases the plasma level of dextromethorphan. Forexample, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, may be administered in an amount that results in a plasmaconcentration of dextromethorphan in the human being, on day 8, that isat least about 2 times, at least about 5 times, at least about 10 times,at least about 15 times, at least about 20 times, at least about 30times, at least about 40 times, at least about 50 times, at least about60 times, at least about 70 times, or at least about 80 times, theplasma concentration of the same amount of dextromethorphan administeredwithout bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may administered to a human being inan amount that results in a 12 hour area under the curve from the timeof dosing (AUC₀₋₁₂), or average plasma concentration in the human beingfor the 12 hours following dosing (C_(avg)) of dextromethorphan, on day8, that is at least about 2 times, at least about 5 times, at leastabout 10 times, at least about 15 times, at least about 20 times, atleast about 30 times, at least about 40 times, at least about 50 times,at least about 60 times, at least about 70 times, or at least about 80times the plasma concentration of the same amount of dextromethorphanadministered without bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may administered to a human being inan amount that results in a maximum plasma concentration (C_(max)) ofdextromethorphan in the human being, on day 8, that is at least about 2times, at least about 5 times, at least about 10 times, at least about15 times, at least about 20 times, at least about 30 times, or at leastabout 40 times the plasma concentration of the same amount ofdextromethorphan administered without bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

For co-administration of bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, an increase in the dextromethorphanplasma level can occur on the first day that bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, is administered, ascompared to the same amount of dextromethorphan administered withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite of prodrug of any of thesecompounds. For example, the dextromethorphan plasma level on the firstday that bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 times, at leastabout at least 2 times, at least about 2.5 times, at least about 3times, at least about 4 times, at least about 5 times, at least about 6times at least about 7 times, at least about 8 times, at least about 9times, or at least about 10 times the level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, the dextromethorphan AUC on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least twice the AUC that would beachieved by administering the same amount of dextromethorphan withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 15 ng·hr/mL, at leastabout 17 ng·hr/mL, at least about 19 ng·hr/mL, at least about 20ng·hr/mL, at least about 22 ng·hr/mL, at least about 23 ng·hr/mL, atleast about 24 ng·hr/mL, at least about 25 ng·hr/mL, at least about 26ng·hr/mL, at least about 27 ng·hr/mL, at least about 28 ng·hr/mL, atleast about 29 ng·hr/mL, at least about 30 ng·hr/mL, at least about 31ng·hr/mL, at least about 32 ng·hr/mL, at least about 33 ng·hr/mL, atleast about 34 ng·hr/mL, at least about 35 ng·hr/mL, at least about 36ng·hr/mL, at least about 37 ng·hr/mL, at least about 38 ng·hr/mL, atleast about 39 ng·hr/mL, at least about 40 ng·hr/mL, at least about 41ng·hr/mL, at least about 42 ng·hr/mL, at least about 43 ng·hr/mL, atleast about 44 ng·hr/mL, at least about 45 ng·hr/mL, at least about 46ng·hr/mL, at least about 47 ng·hr/mL, at least about 48 ng·hr/mL, atleast about 49 ng·hr/mL, at least about 50 ng·hr/mL, at least about 51ng·hr/mL, at least about 52 ng·hr/mL, at least about 53 ng·hr/mL, atleast about 54 ng·hr/mL, at least about 55 ng·hr/mL, at least about 56ng·hr/mL, at least about or 56.7 ng·hr/mL, and may be up to 10,000ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₁₂ on the eighth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 40 ng·hr/mL, at leastabout 50 ng·hr/mL, at least about 60 ng·hr/mL, at least about 70ng·hr/mL, at least about 80 ng·hr/mL, at least about 90 ng·hr/mL, atleast about 100 ng·hr/mL, at least about 150 ng·hr/mL, at least about200 ng·hr/mL, at least about 250 ng·hr/mL, at least about 300 ng·hr/mL,at least about 350 ng·hr/mL, at least about 400 ng·hr/mL, at least about450 ng·hr/mL, at least about 500 ng·hr/mL, at least about 550 ng·hr/mL,at least about 600 ng·hr/mL, at least about 650 ng·hr/mL, at least about700 ng·hr/mL, at least about 750 ng·hr/mL, at least about 800 ng·hr/mL,at least about 850 ng·hr/mL, at least about 900 ng·hr/mL, at least about950 ng·hr/mL, at least about 1000 ng·hr/mL, at least about 1050ng·hr/mL, at least about 1100 ng·hr/mL, at least about 1150 ng·hr/mL, atleast about 1200 ng·hr/mL, at least about 1250 ng·hr/mL, at least about1300 ng·hr/mL, at least about 1350 ng·hr/mL, at least about 1400ng·hr/mL, at least about 1450 ng·hr/mL, at least about 1500 ng·hr/mL, atleast about 1550 ng·hr/mL, at least about 1600 ng·hr/mL, at least about1625 ng·hr/mL, at least about 1650 ng·hr/mL, at least about 1675ng·hr/mL, or at least about 1686.3 ng·hr/mL, and, in some embodiments,may be up to about 50,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC₀₋₂₄ on the eighth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 50 ng·hr/mL, at leastabout 75 ng·hr/mL, at least about 100 ng·hr/mL, at least about 200ng·hr/mL, at least about 300 ng·hr/mL, at least about 400 ng·hr/mL, atleast about 500 ng·hr/mL, at least about 600 ng·hr/mL, at least about700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL,at least about 1000 ng·hr/mL, at least about 1100 ng·hr/mL, at leastabout 1200 ng·hr/mL, at least about 1300 ng·hr/mL, at least about 1400ng·hr/mL, at least about 1500 ng·hr/mL, at least about 1600 ng·hr/mL, atleast about 1700 ng·hr/mL, at least about 1800 ng·hr/mL, at least about1900 ng·hr/mL, at least about 2000 ng·hr/mL, at least about 2100ng·hr/mL, at least about 2200 ng·hr/mL, at least about 2300 ng·hr/mL, atleast about 2400 ng·hr/mL, at least about 2500 ng·hr/mL, at least about2600 ng·hr/mL, at least about 2700 ng·hr/mL, at least about 2800ng·hr/mL, at least about 1850 ng·hr/mL, at least about 2900 ng·hr/mL, atleast about 2950 ng·hr/mL, or at least about 2975.3 ng·hr/mL, and, insome embodiments, may be up to about 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan AUC_(0-inf) on the eighth daythat bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 75 ng·hr/mL, at leastabout 100 ng·hr/mL, at least about 200 ng·hr/mL, at least about 300ng·hr/mL, at least about 400 ng·hr/mL, at least about 500 ng·hr/mL, atleast about 600 ng·hr/mL, at least about 700 ng·hr/mL, at least about800 ng·hr/mL, at least about 900 ng·hr/mL, at least about 1000 ng·hr/mL,at least about 1100 ng·hr/mL, at least about 1200 ng·hr/mL, at leastabout 1300 ng·hr/mL, at least about 1400 ng·hr/mL, at least about 1500ng·hr/mL, at least about 1600 ng·hr/mL, at least about 1700 ng·hr/mL, atleast about 1800 ng·hr/mL, at least about 1900 ng·hr/mL, at least about2000 ng·hr/mL, at least about 2100 ng·hr/mL, at least about 2200ng·hr/mL, at least about 2300 ng·hr/mL, at least about 2400 ng·hr/mL, atleast about 2500 ng·hr/mL, at least about 2600 ng·hr/mL, at least about2700 ng·hr/mL, at least about 2800 ng·hr/mL, at least about 2900ng·hr/mL, at least about 3000 ng·hr/mL, at least about 3100 ng·hr/mL, atleast about 3200 ng·hr/mL, at least about 3300 ng·hr/mL, at least about3400 ng·hr/mL, at least about 3500 ng·hr/mL, at least about 3600ng·hr/mL, at least about 3700 ng·hr/mL, at least about 3800 ng·hr/mL, atleast about 3900 ng·hr/mL, at least about 4000 ng·hr/mL, at least about4100 ng·hr/mL, at least about 4200 ng·hr/mL, at least about 4300ng·hr/mL, at least about 4400 ng·hr/mL, at least about 4500 ng·hr/mL, atleast about 4600 ng·hr/mL, at least about 4700 ng·hr/mL, at least about4800 ng·hr/mL, at least about 4900 ng·hr/mL, at least about 5000ng·hr/mL, at least about 5100 ng·hr/mL, at least about 5200 ng·hr/mL, atleast about 5300 ng·hr/mL, at least about 5400 ng·hr/mL, at least about5500 ng·hr/mL, at least about 5600 ng·hr/mL, at least about 5700ng·hr/mL, at least about 5800 ng·hr/mL, at least about 5900 ng·hr/mL, atleast about 6000 ng·hr/mL, at least about 6100 ng·hr/mL, at least about6200 ng·hr/mL, at least about 6300 ng·hr/mL, at least about 6400ng·hr/mL, at least about 6500 ng·hr/mL, at least about 6600 ng·hr/mL, atleast about 6700 ng·hr/mL, at least about 6800 ng·hr/mL, at least about6900 ng·hr/mL, at least about 7000 ng·hr/mL, at least about 7100ng·hr/mL, at least about 7150 ng·hr/mL, at least about 7200 ng·hr/mL, orat least about 7237.3 ng·hr/mL, and, in some embodiments, may be up toabout 100,000 ng·hr/mL.

In some embodiments, the dextromethorphan C_(max) on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least twice the C_(max) that wouldbe achieved by administering the same amount of dextromethorphan withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, the dextromethorphan C_(max) on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.0 ng/mL, at leastabout 1.5 ng/mL, at least about 2.0 ng/mL, at least about 2.5 ng/mL, atleast about 3.0 ng/mL, at least about 3.1 ng/mL, at least about 3.2ng/mL, at least about 3.3 ng/mL, at least about 3.4 ng/mL, at leastabout 3.5 ng/mL, at least about 3.6 ng/mL, at least about 3.7 ng/mL, atleast about 3.8 ng/mL, at least about 3.9 ng/mL, at least about 4.0ng/mL, at least about 4.1 ng/mL, at least about 4.2 ng/mL, at leastabout 4.3 ng/mL, at least about 4.4 ng/mL, at least about 4.5 ng/mL, atleast about 4.6 ng/mL, at least about 4.7 ng/mL, at least about 4.8ng/mL, at least about 4.9 ng/mL, at least about 5.0 ng/mL, at leastabout 5.1 ng/mL, at least about 5.2 ng/mL, at least about 5.3 ng/mL, atleast about 5.4 ng/mL, at least about 5.5 ng/mL, at least about 5.6ng/mL, at least about 5.7 ng/mL, at least about 5.8 ng/mL, at leastabout 5.9 ng/mL, at least about 6.0 ng/mL, at least about 6.1 ng/mL, atleast about 6.2 ng/mL, at least about 6.3 ng/mL, at least about 6.4ng/mL, at least about 6.5 ng/mL, at least about 6.6 ng/mL, at leastabout 6.7 ng/mL, at least about 6.8 ng/mL, at least about 6.9 ng/mL, atleast about 7.0 ng/mL, at least about 7.1 ng/mL, at least about 7.2ng/mL, at least about 7.3 ng/mL, at least about 7.4 ng/mL, at leastabout 7.5 ng/mL, at least about 7.6 ng/mL, at least about 7.7 ng/mL, atleast about 7.8 ng/mL, at least about 7.9 ng/mL, at least about 8.0ng/mL, at least about 8.1 ng/mL, at least about 8.2 ng/mL, at leastabout 8.3 ng/mL, at least about 8.4 ng/mL, at least about 8.5 ng/mL, atleast about 8.6 ng/mL, or at least about 8.7 ng/mL, and, in someembodiments, may be up to about 1000 ng·hr/mL.

In some embodiments, the dextromethorphan C_(max) on the eighth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 6.0 ng/mL, at leastabout 7.0 ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, atleast about 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL,at least about 25 ng/mL, at least about 30 ng/mL, at least about 35ng/mL, at least about 40 ng/mL, at least about 45 ng/mL, at least about50 ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at leastabout 65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, atleast about 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL,at least about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, at least about 145ng/mL, at least about 150 ng/mL, at least about 155 ng/mL, or at leastabout 158.1 ng/mL, and, in some embodiments, may be up to about 10,000ng/mL.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered in an amount that results in a C_(avg) ofdextromethorphan, over the period between two separate and consecutiveadministrations of dextromethorphan, that is at least about 4.0 ng/mL,at least about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, atleast about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at leastabout 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, atleast about 135 ng/mL, at least about 140 ng/mL, or at least about 140.5ng/mL, and, in some embodiments, may be up to about 10,000 ng/mL. Forexample, if dextromethorphan is administered at 8 am and at 8 pm on day1, and no dextromethorphan is administered after 8 am and before 8 pm onday 1, the period between two separate and consecutive administrationsof dextromethorphan is from immediately after 8 am to immediately before8 pm on day 1.

In some embodiments, the dextromethorphan C_(avg) on the eighth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 4.0 ng/mL, at leastabout 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0 ng/mL, atleast about 8.0 ng/mL, at least about 9.0 ng/mL, at least about 10ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, at least about25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at leastabout 40 ng/mL, at least about 45 ng/mL, at least about 50 ng/mL, atleast about 55 ng/mL, at least about 60 ng/mL, at least about 65 ng/mL,at least about 70 ng/mL, at least about 75 ng/mL, at least about 80ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, at least about95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at leastabout 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, atleast about 125 ng/mL, at least about 130 ng/mL, at least about 135ng/mL, at least about 140 ng/mL, or at least about 140.5 ng/mL, and, insome embodiments, may be up to about 10,000 ng/mL. The C_(avg) valuesgiven above can be for the period between two separate and consecutiveadministrations of dextromethorphan, or if dextromethorphan isadministered only once on Day 8, the C_(avg) can be for 12 hours afterthe first dose of dextromethorphan

In some embodiments, the dextromethorphan trough level (e.g. plasmalevel 12 hours after administration; also referred herein as “C_(min)”)on the first day that bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, is administered may be at least twicethe trough level that would be achieved by administering the same amountof dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, the dextromethorphan C_(min) on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 0.8 ng/mL, at leastabout 0.9 ng/mL, at least about 1.0 ng/mL, at least about 1.1 ng/mL, atleast about 1.2 ng/mL, at least about 1.3 ng/mL, at least about 1.4ng/mL, at least about 1.5 ng/mL, at least about 1.6 ng/mL, at leastabout 1.7 ng/mL, at least about 1.8 ng/mL, at least about 1.9 ng/mL, atleast about 2.0 ng/mL, at least about 2.1 ng/mL, at least about 2.2ng/mL, at least about 2.3 ng/mL, at least about 2.4 ng/mL, at leastabout 2.5 ng/mL, or at least about 2.5 ng/mL, and may be up to about 100ng/mL.

In some embodiments, the dextromethorphan C_(min) on the fifth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 ng/mL, at leastabout 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, atleast about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, or at least about 80.9 ng/mL, and may be up to about10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the sixth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 ng/mL, at leastabout 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, atleast about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, atleast about 95 ng/mL, at least about 100 ng/mL, or at least about 102.2ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the seventh daythat bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 ng/mL, at leastabout 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, atleast about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, atleast about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, or at least about 110.6 ng/mL, and maybe up to about 10,000 ng/mL.

In some embodiments, the dextromethorphan C_(min) on the eighth day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 ng/mL, at leastabout 2.0 ng/mL, at least about 3.0 ng/mL, at least about 4.0 ng/mL, atleast about 5.0 ng/mL, at least about 6.0 ng/mL, at least about 7.0ng/mL, at least about 8.0 ng/mL, at least about 9.0 ng/mL, at leastabout 10 ng/mL, at least about 15 ng/mL, at least about 20 ng/mL, atleast about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL,at least about 40 ng/mL, at least about 45 ng/mL, at least about 50ng/mL, at least about 55 ng/mL, at least about 60 ng/mL, at least about65 ng/mL, at least about 70 ng/mL, at least about 75 ng/mL, at leastabout 80 ng/mL, at least about 85 ng/mL, at least about 90 ng/mL, atleast about 95 ng/mL, at least about 100 ng/mL, at least about 105ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, or at leastabout 119.3 ng/mL, and may be up to about 10,000 ng/mL.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, and dextromethorphan areco-administered, as compared to the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds. For example, the dextrorphan plasma level on the first daymay be reduced by at least 5% as compared to the dextrorphan plasmalevel that would be achieved by administering the same amount ofdextromethorphan without bupropion.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, are co-administered for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite of prodrug of any of thesecompounds, for five consecutive days. For example, the dextromethorphanplasma level on the fifth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 40 times, at least 50 times,at least 60 times, at least 65 times, or up to about 500 times, thelevel that would be achieved by administering the same amount ofdextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for five consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sixconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the sixth day, the dextromethorphan plasmalevel is higher than the dextromethorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for six consecutive days. For example, the dextromethorphanplasma level on the sixth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 30 times, at least 50 times,at least 60 times, at least 70 times, at least 75 times, or up to about500 times, the level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for six consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sevenconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the seventh day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for seven consecutive days. For example, the dextromethorphanplasma level on the seventh day (for example at 0 hours, 1 hour, 3hours, 6 hours, or 12 hours after administration) may be at least 5times, at least 10 times, at least 20 times, at least 30 times, at least50 times, at least 70 times, at least 80 times, at least 90 times, or upto about 500 times, the level that would be achieved by administeringthe same amount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for seven consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least eightconsecutive days, wherein, on the eighth day, dextromethorphan has aplasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12hours, after co-administering bupropion with dextromethorphan that is atleast 5 times, at least 10 times, at least 20 times, at least 30 times,at least 50 times, at least 60 times, at least 70 times, at least 80times, at least 90 times, at least 100 times, or up to about 1,000times, the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for eight consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan are co-administered for at least eightconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the eighth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for eight consecutive days. For example, the dextrorphanplasma level on the eighth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be reduced by at least10%, at least 20%, at least 30%, at least 40%, or at least 50%, ascompared to the dextrorphan plasma level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, for eight consecutivedays.

In some embodiments, bupropion may be administered to a human being inan amount that results in an AUC₀₋₁₂ of bupropion in the human being, onday 8, that is at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 500 ng·hr/mL, at least about 600 ng·hr/mL, at least about700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL,at least about 1,000 ng·hr/mL, at least about 1,200 ng·hr/mL, at least1,600 ng·hr/mL, or up to about 15,000 ng·hr/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(avg) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL,at least about 70 ng/mL, at least about 80 ng/mL, at least about 90ng/mL, at least about 100 ng/mL, at least 120 ng/mL, or up to about1,500 ng/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(max) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 50 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL,at least about 110 ng/mL, at least about 120 ng/mL, at least about 130ng/mL, at least about 140 ng/mL, at least 200 ng/mL, or up to about1,500 ng/mL.

Some liquid compositions may comprise about 0.0001% (w/v) to about 50%(w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10%(w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5%(w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15%(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15%(w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%(w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about50% (w/v) of bupropion, or any amount of bupropion in a range boundedby, or between, any of these values.

Some liquid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg toabout 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about300 mg of bupropion, or any amount of bupropion in a range bounded by,or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of bupropion, or any amountof bupropion in a range bounded by, or between, any of these values.

Some solid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg toabout 200 mg, about 110 mg to about 140 mg, about 50 mg to about 150 mg,about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200mg, about 150 mg, or about 300 mg of bupropion, or any amount ofbupropion in a range bounded by, or between, any of these values.

In some embodiments, bupropion is administered at a dose that results ina bupropion plasma level of about 0.1 μM to about 10 μM, about 0.1 μM toabout 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma level in arange bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, is administered at a dose that results in ahydroxybupropion plasma level of about 0.1 μM to about 10 μM, about 0.1μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM,about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or anyplasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in an AUC₀₋₁₂ of hydroxybupropion in the human being, on day 8,that is at least about 3,000 ng·hr/mL, at least about 7,000 ng·hr/mL, atleast about 10,000 ng·hr/mL, at least about 15,000 ng·hr/mL, at leastabout 20,000 ng·hr/mL, at least about 30,000 ng·hr/mL, up to about50,000 ng·hr/mL, up to about 150,000 ng·hr/mL, or any AUC in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(max) of hydroxybupropion in the human being, on day 8,that is at least about 300 ng/mL, at least about 700 ng/mL, at leastabout 1,000 ng/mL, at least about 1,500 ng/mL, at least about 2,000ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about50,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(avg) of hydroxybupropion in the human being, on day 8,that is at least about 200 ng/mL, at least about 300 ng/mL, at leastabout 700 ng/mL, at least about 1,000 ng/mL, at least about 1,500 ng/mL,at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about10,000 ng/mL, up to about 50,000 ng/mL, or any C_(avg) in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, is administered at a dose that results in athreohydroxybupropion plasma level of about 0.1 μM to about 10 μM, about0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM,about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or anyplasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in an AUC₀₋₁₂ of threohydroxybupropion in the human being,on day 8, that is at least about 1,000 ng·hr/mL, at least about 2,000ng·hr/mL, at least about 4,000 ng·hr/mL, at least about 5,000 ng·hr/mL,at least about 8,000 ng·hr/mL, up to about 10,000 ng·hr/mL, up to about40,000 ng·hr/mL, or any AUC in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(max) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 200 ng/mL, atleast about 400 ng/mL, at least about 500 ng/mL, at least about 600ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about10,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(avg) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 300 ng/mL, atleast about 400 ng/mL, at least about 600 ng/mL, at least about 800ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any C_(avg)in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, is administered at a dose that results in anerythrohydroxybupropion plasma level of about 0.1 μM to about 10 μM,about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM toabout 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM,about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM toabout 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, orany plasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in an AUC₀₋₁₂ of erythrohydroxybupropion in thehuman being, on day 8, that is at least about 200 ng·hr/mL, at leastabout 400 ng·hr/mL, at least about 700 ng·hr/mL, at least about 1,000ng·hr/mL, at least about 1,500 ng·hr/mL, at least about 3,000 ng·hr/mL,up to about 5,000 ng·hr/mL, up to about 30,000 ng·hr/mL, or any plasmalevel in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(max) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 30 ng/mL, at least about 60ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up toabout 1,000 ng/mL, or any C_(max) in a range bounded by, or between, anyof these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(avg) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 20 ng/mL, at least about 30ng/mL, at least about 50 ng/mL, at least about 80 ng/mL, at least about90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at leastabout 200 ng/mL, at least about 300 ng/mL, up to about 1,000 ng/mL, upto about 5,000 ng/mL, or any C_(avg) in a range bounded by, or between,any of these values.

For compositions comprising both dextromethorphan and bupropion, someliquids may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01%(w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v)to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) toabout 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphanand bupropion combined, or any amount in a range bounded by, or between,any of these values. Some solid compositions may comprise at least about5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at leastabout 50% (w/w), at least about 70% (w/w), at least about 80%, about 10%(w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20%(w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30%(w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50%(w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 70%(w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) ofdextromethorphan and bupropion combined, or any amount in a rangebounded by, or between, any of these values. In some embodiments, theweight ratio of dextromethorphan to bupropion in a single composition ordosage form may be about 0.1 to about 2, about 0.2 to about 1, about 0.1to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4,about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, orbetween, any of these values.

A therapeutically effective amount of a therapeutic compound may varydepending upon the circumstances. For example, a daily dose ofdextromethorphan may in some instances range from about 0.1 mg to about1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg,about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mgto about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg,about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg toabout 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg,about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg toabout 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg toabout 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg,about 240 mg, about 360 mg, or any daily dose in a range bounded by, orbetween, any of these values. Dextromethorphan may be administered oncedaily; or twice daily or every 12 hours, three times daily, four timesdaily, or six times daily in an amount that is about half, one third,one quarter, or one sixth, respectively, of the daily dose.

A daily dose of bupropion, may in some instances range from about 10 mgto about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg toabout 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg,about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600mg, or any daily dose in a range bounded by, or between, any of thesevalues. Bupropion may be administered once daily; or twice daily orevery 12 hours, or three times daily in an amount that is about half orone third, respectively, of the daily dose.

In some embodiments: 1) about 50 mg/day to about 100 mg/day, about 100mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day,about 250 mg/day to about 300 mg/day of bupropion, or about 300 mg/dayto about 500 mg/day of bupropion; and/or 2) about 15 mg/day to about 60mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan,are administered to a human being in need thereof.

In some embodiments, about 150 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 90 mg/dayof dextromethorphan, or about 300 mg/day of bupropion and about 120mg/day of dextromethorphan is administered to the human being.

In some embodiments, about 100 mg/day of bupropion and about 15 mg/dayof dextromethorphan is administered to the human being for 1, 2, or 3days, followed by about 200 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 100 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 200 mg/day of bupropion and about60 mg/day of dextromethorphan.

In some embodiments, about 75 mg/day of bupropion and about 15 mg/day ofdextromethorphan is administered to the human being for 1, 2, or 3 days,followed by about 150 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 75 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 150 mg/day of bupropion and about60 mg/day of dextromethorphan.

An antidepressant compound, such as bupropion, may be administered foras long as needed to treat a neurological condition, such as pain,depression or cough. In some embodiments, an antidepressant compound,such as bupropion, and dextromethorphan are administered at least once aday, such as once daily or twice daily, for at least 1 day, at least 3days, at least 5 days, at least 7 days, at least 8 days, at least 14days, at least 30 days, at least 60 days, at least 90 days, at least 180days, at least 365 days, or longer.

Therapeutic compounds may be formulated for oral administration, forexample, with an inert diluent or with an edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, compressed intotablets, or incorporated directly with the food of the diet. For oraltherapeutic administration, the active compound may be incorporated withan excipient and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acid,and the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose, or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

Therapeutic compounds may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also have an oil dispersed within, or dispersed in, glycerol, liquidpolyethylene glycols, and mixtures thereof. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

Specifically Contemplated Embodiments

The following are examples of embodiments that are specificallycontemplated by the inventor:

-   -   Embodiment 1. A method of treating pain or a neurological        disorder comprising administering a therapeutically effective        amount of dextromethorphan and a therapeutically effective        amount of an antidepressant compound, to a person in need        thereof.    -   Embodiment 2. A method of treating pain comprising administering        a combination of an antidepressant compound and dextromethorphan        to a human being in need thereof.    -   Embodiment 3. A method of enhancing the pain relieving        properties of dextromethorphan, comprising co-administering        dextromethorphan and an antidepressant compound.    -   Embodiment 4. A method of increasing dextromethorphan plasma        levels in a human being that is an extensive metabolizer of        dextromethorphan, comprising co-administering an antidepressant        compound to the human being receiving a treatment that includes        administration of dextromethorphan.    -   Embodiment 5. A method of inhibiting the metabolism of        dextromethorphan, comprising administering an antidepressant        compound to a human being, wherein the human being is an        extensive metabolizer of dextromethorphan, and wherein        dextromethorphan is present in the body of the human being at        the same time as the antidepressant compound.    -   Embodiment 6. A method of increasing the metabolic lifetime of        dextromethorphan, comprising administering an antidepressant        compound to a human being, wherein the human being is an        extensive metabolizer of dextromethorphan, and wherein        dextromethorphan is present in the body of the human being at        the same time as the antidepressant compound.    -   Embodiment 7. A method of correcting extensive metabolism of        dextromethorphan, comprising administering an antidepressant        compound to a human being in need thereof.    -   Embodiment 8. A method of improving pain relieving properties of        dextromethorphan comprising administering an antidepressant        compound in conjunction with administration of dextromethorphan        to a human being in need of treatment for pain.    -   Embodiment 9. A method of improving antitussive properties of        dextromethorphan comprising administering an antidepressant        compound in conjunction with administration of dextromethorphan        to a human being in need of treatment for cough.    -   Embodiment 10. A method of treating cough comprising        administering a combination of an antidepressant compound and        dextromethorphan to a human being in need thereof.    -   Embodiment 11. A method of improving a therapeutic property of        dextromethorphan comprising administering an antidepressant        compound in conjunction with administration of dextromethorphan        to a human being in need of treatment for a neurological        disorder.    -   Embodiment 12. A method of treating a neurological disorder        comprising administering a combination of an antidepressant        compound and dextromethorphan to a human being in need thereof.    -   Embodiment 13. A method of treating a neurological disorder        comprising administering an antidepressant compound and        dextromethorphan to a human being in need thereof, wherein the        human being is an extensive metabolizer of dextromethorphan.    -   Embodiment 14. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein        the dextromethorphan and the antidepressant compound are        administered in separate dosage forms.    -   Embodiment 15. A pharmaceutical composition comprising a        therapeutically effective amount of dextromethorphan, a        therapeutically effective amount of an antidepressant compound,        and a pharmaceutically acceptable excipient.    -   Embodiment 16. An oral dosage form comprising at least 20 mg of        dextromethorphan and an effective amount of an antidepressant        compound to inhibit the metabolism of dextromethorphan in a        human being that is an extensive metabolizer of        dextromethorphan.    -   Embodiment 17. The oral dosage form of embodiment 16, wherein        about 30 mg to about 350 mg of dextromethorphan is present in        the dosage form.    -   Embodiment 18. The oral dosage form of embodiment 16 or 17,        wherein about 100 mg to about 400 mg of bupropion is present in        the dosage form.    -   Embodiment 19. The oral dosage form of any of embodiments 16,        17, or 18, comprising an amount of bupropion that results in a        bupropion plasma level of about 0.1 μM to about 10 μM when the        oral dosage form is administered to a human being.    -   Embodiment 20. The oral dosage form of embodiment 19, comprising        an amount of bupropion that results in a bupropion plasma level        of about 0.1 μM to about 2 μM when the oral dosage form is        administered to a human being.    -   Embodiment 21. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein        bupropion is administered at a dose that results in a bupropion        plasma level of about 0.1 μM to about 10 μM.    -   Embodiment 22. The method of any preceding embodiment, such as        embodiment 21, wherein bupropion is administered at a dose that        results in a bupropion plasma level of about 0.3 μM to about 1        μM.    -   Embodiment 23. The method, composition, or dosage form of any        preceding embodiment, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8,        9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant        compound is bupropion or a metabolite thereof.    -   Embodiment 24. The method, composition, or dosage form of any        preceding embodiment, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8,        9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant        compound is bupropion.    -   Embodiment 25. The method, composition, or dosage form of any        preceding embodiment, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8,        9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant        compound is clomipramine, doxepin, fluoxetine, mianserin,        imipramine, 2-chloroimipramine, amitriptyline, amoxapine,        desipramine, protriptyline, trimipramine, nortriptyline,        maprotiline, phenelzine, isocarboxazid, tranylcypromine,        paroxetine, trazodone, citalopram, sertraline, aryloxy        indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine,        desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline,        or a pharmaceutically acceptable salt thereof    -   Embodiment 26. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 21, 22, 23,        24, or 25, wherein dextromethorphan is administered to the human        being for the treatment of cough.    -   Embodiment 27. A method of treating a neurological disorder        comprising administering about 150 mg/day to about 300 mg/day of        bupropion and about 30 mg/day to about 120 mg/day of        dextromethorphan to a human being in need thereof.    -   Embodiment 28. A method of treating a neurological disorder        comprising administering bupropion and dextromethorphan to a        human being in need thereof, wherein the bupropion and        dextromethorphan are administered at least once a day for at        least 8 days.    -   Embodiment 29. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, or 27, wherein bupropion is administered to        the human being at least daily for at least 8 days.    -   Embodiment 30. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, or 28, wherein dexromethorphan is        administered to the human being at least daily for at least 8        days.    -   Embodiment 31. The method of any preceding embodiment, such as        embodiment 28, 29, or 30, wherein bupropion is administered in        an amount that results in a plasma concentration of        dextromethorphan in the human being, on day 8, that is at least        10 times the plasma concentration of the same amount of        dextromethorphan administered without bupropion.    -   Embodiment 32. The method of any preceding embodiment, such as        embodiment 28, 29, 30, or 31, wherein bupropion is administered        in an amount that results in an AUC₀₋₁₂ of hydroxybupropion, on        day 8, that is at least about 3000 ng·hr/mL.    -   Embodiment 33. The method of any preceding embodiment, such as        embodiment 28, 29, 30, 31, or 32, wherein bupropion is        administered in an amount that results in an AUC₀₋₁₂ of        erythrohydroxybupropion, on day 8, that is at least about 400        ng·hr/mL.    -   Embodiment 34. The method of any preceding embodiment, such as        embodiment 28, 29, 30, 31, 32, or 33, wherein bupropion is        administered in an amount that results in an AUC₀₋₁₂ of        threohydroxybupropion, on day 8, that is at least about 2000        ng·hr/mL.    -   Embodiment 35. The method, composition, or dosage form of any        preceding embodiment, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8,        9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,        26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the weight ratio        of dextromethorphan to bupropion is about 0.1 to about 0.5.    -   Embodiment 36. The method of any preceding embodiment, such as        embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the        human being is an extensive metabolizer of dextromethorphan.    -   Embodiment 37. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 150 mg/day of bupropion and about 30 mg/day of        dextromethorphan is administered to the human being.    -   Embodiment 38. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 150 mg/day of bupropion and about 60 mg/day of        dextromethorphan is administered to the human being.    -   Embodiment 39. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 200 mg/day of bupropion and about 30 mg/day of        dextromethorphan is administered to the human being.    -   Embodiment 40. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 100 mg/day of bupropion and about 15 mg/day of        dextromethorphan is administered to the human being for about 1        to about 3 days, followed by about 200 mg/day of bupropion and        about 30 mg/day of dextromethorphan.    -   Embodiment 41. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 200 mg/day of bupropion and about 60 mg/day of        dextromethorphan is administered to the human being.    -   Embodiment 42. The method of any preceding embodiment, such as        embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21,        22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,        wherein about 100 mg/day of bupropion and about 30 mg/day of        dextromethorphan is administered to the human being for about 1        to about 3 days, followed by about 200 mg/day of bupropion and        about 60 mg/day of dextromethorphan.    -   Embodiment 43. The method of any preceding embodiment, such as        embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24,        25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,        41, or 42, wherein dextromethorphan is administered to the human        being for the treatment of pain.    -   Embodiment 44. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises postoperative pain,        cancer pain, arthritic pain, lumbosacral pain, musculoskeletal        pain, central multiple sclerosis pain, nociceptive pain, or        neuropathic pain.    -   Embodiment 45. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises musculoskeletal pain,        neuropathic pain, cancer-related pain, acute pain, or        nociceptive pain.    -   Embodiment 46. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises postoperative pain.    -   Embodiment 47. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises cancer pain.    -   Embodiment 48. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises arthritic pain.    -   Embodiment 49. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises lumbosacral pain.    -   Embodiment 50. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises musculoskeletal pain.    -   Embodiment 51. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises neuropathic pain.    -   Embodiment 52. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises nociceptive pain.    -   Embodiment 53. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises chronic        musculoskeletal pain.    -   Embodiment 54. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with rheumatoid        arthritis.    -   Embodiment 55. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with juvenile        rheumatoid arthritis.    -   Embodiment 56. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with        osteoarthritis.    -   Embodiment 57. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with an axial        spondyloarthritis.    -   Embodiment 58. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with ankylosing        spondylitis.    -   Embodiment 59. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with diabetic        peripheral neuropathy.    -   Embodiment 60. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with post-herpetic        neuralgia.    -   Embodiment 61. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with trigeminal        neuralgia.    -   Embodiment 62. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with        monoradiculopathies.    -   Embodiment 63. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with phantom limb        pain.    -   Embodiment 64. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with central pain.    -   Embodiment 65. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises cancer-related pain.    -   Embodiment 66. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with lumbar nerve        root compression.    -   Embodiment 67. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with spinal cord        injury.    -   Embodiment 68. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with post-stroke        pain.    -   Embodiment 69. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with central        multiple sclerosis pain.    -   Embodiment 70. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with        HIV-associated neuropathy.    -   Embodiment 71. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with radio-therapy        associated neuropathy.    -   Embodiment 72. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with chemo-therapy        associated neuropathy.    -   Embodiment 73. The method of any preceding embodiment, such as        embodiment 43, wherein the pain comprises dental pain.    -   Embodiment 74. The method of any preceding embodiment, such as        embodiment 43, wherein the pain is associated with primary        dysmenorrhea.    -   Embodiment 75. The method of any preceding embodiment, such as        embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24,        25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,        41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,        57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,        73, or 74, wherein 90 mg/day of dextromethorphan is administered        to the human being.    -   Embodiment 76. The method of any preceding embodiment, such as        embodiment 75, wherein 45 mg of dextromethorphan is administered        twice a day to the human being.    -   Embodiment 77. The method of any preceding embodiment, such as        embodiment 75 or 76, wherein 150 mg/day of bupropion is        administered to the human being.    -   Embodiment 78. The method of any preceding embodiment, such as        embodiment 75 or 76, wherein 180 mg/day of bupropion is        administered to the human being.    -   Embodiment 79. The method of any preceding embodiment, such as        embodiment 75 or 76, wherein 200 mg/day of bupropion is        administered to the human being.    -   Embodiment 80. The method of any preceding embodiment, such as        embodiment 123 or 124, wherein 300 mg/day of bupropion is        administered to the human being.    -   Embodiment 81. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, with        dextromethorphan to the human being, wherein the        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, is        administered in an amount that results in an AUC₀₋₁₂ of        dextromethorphan that is at least about 40 ng·hr/mL.    -   Embodiment 82. The method of any preceding embodiment, such as        embodiment 81, wherein the AUC₀₋₁₂ of dextromethorphan is at        least about 50 ng·hr/mL.    -   Embodiment 83. The method of any preceding embodiment, such as        embodiment 81 or 82, wherein the human being is in need of        treatment with dextromethorphan.    -   Embodiment 84. The method of any preceding embodiment, such as        embodiment 81, 82, or 83, wherein the human being is an        extensive metabolizer of dextromethorphan.    -   Embodiment 85. The method of any preceding embodiment, such as        embodiment 81, 82, 83, or 84, wherein the threohydroxybupropion,        hydroxybupropion, erythrohydroxybupropion, bupropion, or a        prodrug thereof, and dextromethorphan are administered to the        human being at least daily for at least 8 days.    -   Embodiment 86. The method of any preceding embodiment, such as        embodiment 85, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8        is at least about 100 ng·hr/mL.    -   Embodiment 87. The method of any preceding embodiment, such as        embodiment 85 or 86, wherein the AUC₀₋₁₂ of dextromethorphan on        Day 8 is at least about 400 ng·hr/mL.    -   Embodiment 88. The method of any preceding embodiment, such as        embodiment 85, 86, or 87, wherein the AUC₀₋₁₂ of        dextromethorphan on Day 8 is at least about 800 ng·hr/mL.    -   Embodiment 89. The method of any preceding embodiment, such as        embodiment 85, 86, 87, or 88, wherein the AUC₀₋₁₂ of        dextromethorphan on Day 8 is at least about 1500 ng·hr/mL.    -   Embodiment 90. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, or 89, wherein the AUC₀₋₂₄ of        dextromethorphan on Day 8 is at least about 100 ng·hr/mL.    -   Embodiment 91. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, or 90, wherein the AUC₀₋₂₄ of        dextromethorphan on Day 8 is at least about 1500 ng·hr/mL.    -   Embodiment 92. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, 90, or 91, wherein the AUC₀₋₂₄ of        dextromethorphan on Day 8 is at least about 2900 ng·hr/mL.    -   Embodiment 93. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, 90, 91, or 92, wherein the        AUC_(0-inf) of dextromethorphan on Day 8 is at least about 100        ng·hr/mL.    -   Embodiment 94. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, 90, 91, 92, or 93, wherein the        AUC_(0-inf) of dextromethorphan on Day 8 is at least about 1500        ng·hr/mL.    -   Embodiment 95. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, 90, 91, 92, 93, or 94, wherein        the AUC_(0-inf) of dextromethorphan on Day 8 is at least about        3500 ng·hr/mL.    -   Embodiment 96. The method of any preceding embodiment, such as        embodiment 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95,        wherein the AUC_(0-inf) of dextromethorphan on Day 8 is at least        about 5000 ng·hr/mL.    -   Embodiment 97. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, with        dextromethorphan to the human being, wherein the        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, is        administered in an amount that results in a C_(max) of        dextromethorphan that is at least about 6 ng/mL.    -   Embodiment 98. The method of any preceding embodiment, such as        embodiment 97, wherein the human being is in need of treatment        with dextromethorphan.    -   Embodiment 99. The method of any preceding embodiment, such as        embodiment 97 or 98, wherein the human being is an extensive        metabolizer of dextromethorphan.    -   Embodiment 100. The method of any preceding embodiment, such as        embodiment 97, 98, or 99, wherein the threohydroxybupropion,        hydroxybupropion, erythrohydroxybupropion, bupropion, or a        prodrug thereof, and dextromethorphan are administered to the        human being at least daily for at least 8 days.    -   Embodiment 101. The method of any preceding embodiment, such as        embodiment 100, wherein the C_(max) of dextromethorphan on Day 8        is at least about 20 ng/mL.    -   Embodiment 102. The method of any preceding embodiment, such as        embodiment 100 or 101, wherein the C_(max) of dextromethorphan        on Day 8 is at least about 60 ng/mL.    -   Embodiment 103. The method of any preceding embodiment, such as        embodiment 100, 101, or 102, wherein the C_(max) of        dextromethorphan on Day 8 is at least about 120 ng/mL.    -   Embodiment 104. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, with        dextromethorphan to the human being, wherein the        threohydroxybupropion, hydroxybupropion,        erythrohydroxybupropion, bupropion, or a prodrug thereof, is        administered in an amount that results in a C_(avg) of        dextromethorphan over a 12 hour period, after one        administration, that is at least about 5 ng/mL.    -   Embodiment 105. The method of any preceding embodiment, such as        embodiment 104, wherein the human being is in need of treatment        with dextromethorphan.    -   Embodiment 106. The method of any preceding embodiment, such as        embodiment 104 or 105, wherein the human being is an extensive        metabolizer of dextromethorphan.    -   Embodiment 107. The method of any preceding embodiment, such as        embodiment 104, 105, or 106, wherein the threohydroxybupropion,        hydroxybupropion, erythrohydroxybupropion, bupropion, or a        prodrug thereof, and dextromethorphan are administered to the        human being at least daily for at least 8 days.    -   Embodiment 108. The method of any preceding embodiment, such as        embodiment 107, wherein the C_(avg) of dextromethorphan on Day 8        is at least about 20 ng/mL.    -   Embodiment 109. The method of any preceding embodiment, such as        embodiment 107 or 108, wherein the C_(avg) of dextromethorphan        on Day 8 is at least about 70 ng/mL.    -   Embodiment 110. The method of any preceding embodiment, such as        embodiment 107, 108, or 109, wherein the C_(avg) of        dextromethorphan on Day 8 is at least about 120 ng/mL.    -   Embodiment 111. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering bupropion,        hydroxybupropion, erythrohydroxybupropion,        threohydroxybupropion, or a prodrug of any of these compounds,        with dextromethorphan to the human being, wherein the bupropion        or a prodrug thereof is administered in an amount that results        in an AUC₀₋₁₂ of dextromethorphan that is at least about 40        ng·hr/mL.    -   Embodiment 112. The method of any preceding embodiment, such as        embodiment 111, wherein the AUC₀₋₁₂ of dextromethorphan is at        least about 50 ng·hr/mL.    -   Embodiment 113. The method of any preceding embodiment, such as        embodiment 111 or 112, wherein the human being is in need of        treatment with dextromethorphan.    -   Embodiment 114. The method of any preceding embodiment, such as        embodiment 111, 112, or 113, wherein the human being is an        extensive metabolizer of dextromethorphan.    -   Embodiment 115. The method of any preceding embodiment, such as        embodiment 111, 112, 113, or 114, wherein the bupropion or a        prodrug thereof is co-administered with dextromethorphan at        least daily for at least two consecutive days.    -   Embodiment 116. The method of any preceding embodiment, such as        embodiment 115, wherein the bupropion or a prodrug thereof and        dextromethorphan are administered to the human being at least        daily for at least 8 days.    -   Embodiment 117. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8        is at least about 100 ng·hr/mL.    -   Embodiment 118. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8        is at least about 800 ng·hr/mL.    -   Embodiment 119. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC₀₋₁₂ of dextromethorphan on Day 8        is at least about 1500 ng·hr/mL.    -   Embodiment 120. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC₀₋₂₄ of dextromethorphan on Day 8        is at least about 100 ng·hr/mL.    -   Embodiment 121. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC₀₋₂₄ of dextromethorphan on Day 8        is at least about 1500 ng·hr/mL.    -   Embodiment 122. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC_(0-inf) of dextromethorphan on        Day 8 is at least about 100 ng·hr/mL.    -   Embodiment 123. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC_(0-inf) of dextromethorphan on        Day 8 is at least about 3500 ng·hr/mL.    -   Embodiment 124. The method of any preceding embodiment, such as        embodiment 116, wherein the AUC_(0-inf) of dextromethorphan on        Day 8 is at least about 5000 ng·hr/mL.    -   Embodiment 125. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering bupropion,        hydroxybupropion, erythrohydroxybupropion,        threohydroxybupropion, or a prodrug of any of these compounds,        with dextromethorphan to the human being, wherein the bupropion        or a prodrug thereof is administered in an amount that results        in a C_(max) of dextromethorphan that is at least about 6 ng/mL.    -   Embodiment 126. The method of any preceding embodiment, such as        embodiment 125, wherein the human being is in need of treatment        with dextromethorphan.    -   Embodiment 127. The method of any preceding embodiment, such as        embodiment 125 or 126, wherein the human being is an extensive        metabolizer of dextromethorphan.    -   Embodiment 128. The method of any preceding embodiment, such as        embodiment 126, 127, or 128, wherein the bupropion or a prodrug        thereof is co-administered with dextromethorphan at least daily        for at least two consecutive days.    -   Embodiment 129. The method of any preceding embodiment, such as        embodiment 128, wherein the bupropion or a prodrug thereof and        dextromethorphan are administered to the human being at least        daily for at least 8 days.    -   Embodiment 130. The method of any preceding embodiment, such as        embodiment 129, wherein the C_(max) of dextromethorphan on Day 8        is at least about 10 ng/mL.    -   Embodiment 131. The method of any preceding embodiment, such as        embodiment 129, wherein the C_(max) of dextromethorphan on Day 8        is at least about 60 ng/mL.    -   Embodiment 132. The method of any preceding embodiment, such as        embodiment 129, wherein the C_(max) of dextromethorphan on Day 8        is at least about 120 ng/mL.    -   Embodiment 133. A method of increasing dextromethorphan plasma        levels in a human being, comprising co-administering bupropion,        hydroxybupropion, erythrohydroxybupropion,        threohydroxybupropion, or a prodrug of any of these compounds,        with dextromethorphan to the human being, wherein the bupropion        or a prodrug thereof is administered in an amount that results        in a C_(avg) of dextromethorphan, over the period between two        separate and consecutive administrations of dextromethorphan,        that is at least about 5 ng/mL.    -   Embodiment 134. The method of any preceding embodiment, such as        embodiment 134, wherein the bupropion or a prodrug thereof is        administered in an amount that results in a C_(avg) of        dextromethorphan, over the period between two separate and        consecutive administrations of dextromethorphan, that is at        least about 60 ng/mL.    -   Embodiment 135. The method of any preceding embodiment, such as        embodiment 134, wherein the human being is in need of treatment        with dextromethorphan.    -   Embodiment 136. The method of any preceding embodiment, such as        embodiment 134 or 135, wherein the human being is an extensive        metabolizer of dextromethorphan.    -   Embodiment 137. The method of any preceding embodiment, such as        embodiment 134, 135, or 136, wherein the bupropion or a prodrug        thereof is co-administered with dextromethorphan at least daily        for at least two consecutive days.    -   Embodiment 138. The method of any preceding embodiment, such as        embodiment 137, wherein the bupropion or a prodrug thereof and        dextromethorphan are administered to the human being at least        daily for at least 8 days.    -   Embodiment 139. The method of any preceding embodiment, such as        embodiment 138, wherein the C_(avg) of dextromethorphan on Day 8        is at least about 8 ng/mL,        -   wherein the C_(avg) is for the period between two separate            and consecutive administrations of dextromethorphan, or        -   if dextromethorphan is administered only once on Day 8, the            C_(avg) is for 12 hours after the first dose of            dextromethorphan on Day 8.    -   Embodiment 140. The method of any preceding embodiment, such as        embodiment 138, wherein the C_(avg) of dextromethorphan on Day 8        is at least about 120 ng/mL,        -   wherein the C_(avg) is for the period between two separate            and consecutive administrations of dextromethorphan, or        -   if dextromethorphan is administered only once on Day 8, the            C_(avg) for 12 hours after the first dose of            dextromethorphan on Day 8.

The following documents are incorporated by reference in their entirety:U.S. Provisional Application No. 61/900,354; PCT Application No.PCT/US2014/64184; U.S. patent application Ser. No. 14/554,947; U.S.patent application Ser. No. 14/554,988; U.S. patent application Ser. No.14/550,618; and U.S. patent application Ser. No. 14/555,085.

EXAMPLES Example 1

Fifteen human subjects were randomized into one of two treatment groupsreceiving either dextromethorphan (DM) alone, or DM in combination withbupropion, as shown in Table 1 below.

TABLE 1 Study Design Dose Levels Dura- Total Group Bupropion/DM DosingRegimen tion Subjects A  0 mg/60 mg DM: Twice daily, Days 8 Days 1-8 1-8B 150 mg/60 mg Bupropion: Once daily, Days 7 Days 1-3; Twice daily, 1-8Days 4-8 DM: Twice daily, Days 1-8

All subjects were extensive, including ultra-rapid, metabolizers ofdextromethorphan as determined by CYP2D6 genetic testing.Dextromethorphan was dosed at 12-hour intervals on Days 1-8, with afinal morning dose on Day 8. Bupropion was dosed once daily on Days 1-3,and at 12-hour intervals thereafter, with a final morning dose on Day 8.

Plasma samples were collected for concentration analysis ofdextromethorphan, total dextrorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8.Plasma samples for determination of trough concentrations ofdextromethorphan were obtained approximately 12 hours after dosing ondays 1, 5, 6, and 8.

Concentrations of dextromethorphan, total dextrorphan (unconjugated andglucuronide forms), bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion, were determinedusing LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of dextromethorphan metabolizer status wasperformed by calculating the dextromethorphan/dextrorphan metabolicratio as described in Jurica et al. Journal of Clinical Pharmacy andTherapeutics, 2012, 37, 486-490. Plasma concentrations ofdextromethorphan and dextrorphan 3 hours after dosing were used, with adextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poormetabolizer phenotype.

Results

Plasma concentrations of dextromethorphan were significantly increasedwith bupropion administration, as illustrated in FIG. 1 and Table 2.

TABLE 2 Mean Day 8 Dextromethorphan Plasma Concentrations (ng/mL) TimeDextromethorphan Dextromethorphan + (hours) (Group A) Bupropion (GroupB) 0 1.2 110.6 1 2.4 129.3 2 3.6 153.9 3 3.6 151.6 4 3.3 149.1 6 2.5150.0 8 1.9 144.4 12 1.1 119.3 24 0.4 95.3 36 0.1 69.0

The AUC of dextromethorphan was significantly increased withadministration of bupropion as show in FIGS. 2-4. As shown in FIG. 5 andTable 2A, administration of bupropion with dextromethorphan resulted inan approximately 60-fold, 80-fold, and 175-fold increase in meandextromethorphan AUC₀₋₁₂, AUC₀₋₂₄, and AUC_(0-inf), respectively on Day8 as compared to administration of dextromethorphan alone. As shown inFIG. 6 and Table 2B, the increase in dextromethorphan AUC occurred asearly as Day 1 (an approximate 3-fold increase in AUC₀₋₁₂).

TABLE 2A Day 8 Values Dextromethorphan Dextromethorphan + (Group A)Bupropion (Group B) AUC₀₋₁₂ (ng*hr/mL) 28.1 1,686.3 AUC₀₋₂₄ (ng*hr/mL)37.1 2,975.3 AUC_(0-inf) (ng*hr/mL) 41.2 7,237.3 C_(max) (ng/mL) 3.8158.1 C_(min) (ng/mL) 1.1 119.3 C_(avg) (ng/mL) 2.3 140.5

TABLE 2B Day 1 Values Dextromethorphan Dextromethorphan + (Group A)Bupropion (Group B) AUC₀₋₁₂ (ng*hr/mL) 20.1 56.5 C_(max) (ng/mL) 3.0 8.7

Trough plasma concentrations (also referred to as “minimum mean plasmaconcentrations” or “C_(min)”) of dextromethorphan were significantlyincreased with administration of bupropion as illustrated in FIG. 7 andTables 2A and 3. Administration of bupropion with dextromethorphanresulted in an approximately 105-fold increase in mean trough plasmaconcentration of dextromethorphan on Day 8 as compared to administrationof dextromethorphan alone.

Mean average plasma concentrations (C_(avg)) of dextromethorphan on Day8 increased approximately 60-fold with bupropion administration ascompared to administration of dextromethorphan alone, as illustrated inTable 2A. Maximum mean plasma concentrations (C_(max)) were alsosignificantly increased as illustrated in FIG. 8 and Table 2A.

TABLE 3 Mean Trough Dextromethorphan Plasma Concentrations (ng/mL)Dextromethorphan Dextromethorphan + Fold (Group A) Bupropion (Group B)Change Day 1 0.7 2.5 3.5 Day 5 1.2 80.9 70 Day 6 1.3 102.2 78 Day 7 1.2110.6 94 Day 8 1.1 119.3 105

The T_(max) and elimination half life (T_(1/2 el)) of dextromethorphanwere significantly increased with administration of bupropion on Day 8.The increase of T_(1/2 el) shows that the metabolic lifetime ofdextromethorphan was increased. Administration of bupropion withdextromethorphan resulted in a mean T_(max) of 3.6 hours, compared to2.3 hours for dextromethorphan alone. Administration of bupropion withdextromethorphan resulted in a mean T_(1/2 el) of 27.7 hours, comparedto 6.6 hours for dextromethorphan alone.

Plasma concentrations of dextrorphan were significantly decreased withbupropion administration, as illustrated in FIG. 9 and Table 4.

TABLE 4 Mean Day 8 Dextrorphan Plasma Concentrations (ng/mL) TimeDextromethorphan Dextromethorphan + (hours) (Group A) Bupropion (GroupB) 0 132.4 165.3 1 688.9 190.7 2 959.1 214.9 3 778.1 214.4 4 594.9 205.16 324.7 172.5 8 189.6 159.6 12 74.8 152.8 24 12.2 133.0 36 0.1 107.6

As shown in FIGS. 10-11, there was an approximate 78% reduction in meandextrorphan C_(max), and an approximate 55% reduction in meandextrorphan AUC₀₋₁₂ on Day 8 with administration of bupropion.

Phenotypic determination of dextromethorphan metabolizer status showedthat no subjects in either treatment arm were poor metabolizers onDay 1. On Day 8 however, 100% of subjects treated with bupropion hadconverted to poor metabolizer status as compared to 0% of subjectstreated with dextromethorphan alone. The mean plasmadextromethorphan/dextrorphan metabolic ratio increased from 0.01 on Day1 to 0.71 on Day 8 with bupropion administration. The mean ratio in thegroup administered DM alone was 0.00 on Day 1 and remained unchanged onDay 8.

On Day 8, average plasma concentrations of bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion were at least 10ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropionadministration.

As used in this section, the term “fold change” or “fold increase”refers to the ratio of a value for bupropion with dextromethorphan tothe same value for dextromethorphan alone (i.e. the value for bupropionwith dextromethorphan divided by the same value for dextromethorphanalone).

Example 2

The ability of various antidepressant compounds to inhibit themetabolism of dextromethorphan was examined using human livermicrosomes. Each antidepressant compound was incubated at sevenincreasing concentrations (0.1-100 μM) in duplicate with human livermicrosomes (0.5 mg/mL) in the presence of dextromethorphan (5 μM) at 37°C. The assay was performed in the presence of 2 mM NADPH in 100 mMpotassium phosphate (pH 7.4) containing 5 mM magnesium chloride, in a200 μl assay final volume.

After optimal incubation at 37° C., the reactions were terminated byaddition of methanol containing internal standard for analyticalquantification. The quenched samples were incubated at 4° C. for 10minutes and centrifuged at 4° C. for 10 minutes. The supernatant wasremoved and the metabolite of dextromethorphan (dextrorphan) wasanalyzed by LC-MS/MS. A decrease in the formation of the metabolitecompared to vehicle control was used to calculate an IC₅₀ value (thetest concentration which produces 50% inhibition of dextromethorphanmetabolism) for each antidepressant compound, with a lower IC₅₀indicating greater potency.

The results are summarized in Table 5 below, and the correspondingpotencies are depicted in FIG. 12.

TABLE 5 Test Compound Mean IC₅₀ (μM) Desvenlafaxine 97.3 Venlafaxine27.7 Escitalopram 17.1 Citalopram 14.1 (2S,3S)-Hydroxybupropion 12.5Bupropion 9.1 (R,R)-Hydroxybupropion 8.2 Fluvoxamine 6.5 Sertraline 5.1(S)-Duloxetine 4.1 Threohydroxybupropion 3.9 Erythrohydroxybupropion 1.4

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

The invention claimed is:
 1. A method of increasing dextromethorphanplasma levels in a human being, comprising co-administering about 150 mgper day to about 500 mg per day of bupropion with dextromethorphan tothe human being for at least eight consecutive days, wherein bupropionand dextromethorphan are administered once or twice a day, wherein thehuman being is an extensive metabolizer of dextromethorphan in need oftreatment with dextromethorphan, and wherein on the eighth day, theco-administration results in an AUC₀₋₁₂ of dextromethorphan that is atleast about 20 times the AUC₀₋₁₂ that would be achieved by administeringthe same amount of dextromethorphan without bupropion for eightconsecutive days.
 2. The method of claim 1, wherein the human being isan extensive metabolizer of dextromethorphan.
 3. The method of claim 2,wherein the AUC₀₋₁₂ of dextromethorphan on Day 8 is at least about 700ng·hr/mL.
 4. The method of claim 2, wherein the AUC₀₋₂₄ ofdextromethorphan on Day 8 is at least about 1000 ng·hr/mL.
 5. The methodof claim 2, wherein the AUC_(0-inf) of dextromethorphan on Day 8 is atleast about 2000 ng·hr/mL.
 6. The method of claim 2, wherein theAUC_(0-inf) of dextromethorphan on Day 8 is at least about 3000ng·hr/mL.
 7. A method of increasing dextromethorphan plasma levels in ahuman being, comprising co-administering about 150 mg per day to about500 mg per day of bupropion with dextromethorphan to the human being forat least eight consecutive days, wherein bupropion and dextromethorphanare administered once or twice a day, wherein the human being is in needof treatment with increased plasma levels of dextromethorphan, andwherein on the eighth day, the co-administration results in a C_(max) ofdextromethorphan that is at least about 20 times the C_(max) that wouldbe achieved by administering the same amount of dextromethorphan withoutbupropion for eight consecutive days.
 8. The method of claim 7, whereinthe human being is an extensive metabolizer of dextromethorphan.
 9. Themethod of claim 8, wherein the C_(max) of dextromethorphan on Day 8 isat least about 80 ng/mL.
 10. A method of increasing dextromethorphanplasma levels in a human being, comprising co-administering about 150 mgper day to about 500 mg per day of bupropion with dextromethorphan tothe human being for at least eight consecutive days, wherein bupropionand dextromethorphan are administered once or twice a day, wherein thehuman being is in need of treatment with increased plasma levels ofdextromethorphan, and wherein on the eighth day, the co-administrationresults in a C_(avg) of dextromethorphan over the period between twoseparate and consecutive administrations of dextromethorphan that is atleast about 20 times the C_(avg) that would be achieved by administeringthe same amount of dextromethorphan without bupropion for eightconsecutive days.
 11. The method of claim 10, wherein the bupropion isadministered in an amount that results in a C_(avg) of dextromethorphan,over the period between two separate and consecutive administrations ofdextromethorphan, that is at least about 60 ng/mL.
 12. The method ofclaim 10, wherein the human being is an extensive metabolizer ofdextromethorphan.